Immune Mosquitos: A Case Study Of Gene Drives
What if you learned that there was a way to stop the greatest killer in history who kills thousands of innocent people every year? What if we could eradicate malaria? Should we implement the GMO created for this purpose?
These questions are only a fraction of those that immuned mosquitoes raise. Because it would indeed be mosquitoes that would be immuned by gene drive, and not us humans.
Why use gene drive on mosquitoes?
Here’s why: malaria is caused by a collection of single-celled, parasitic microorganisms. Mosquitoes serve as their transport from one victim to another. At the start of a cycle, an infected mosquito bites a person for their blood supply. The insect is sick, but does not show any symptoms. This is possible because the same diseases do not manifest themselves in the same way in all organisms. At this point, the parasites invade the human body and make their way to the liver, where they burrow for a while. What are they doing there? They feed on some of the cells that make it up, killing them in the process. They multiply in their interior, creating thousands of copies of themselves. After a month at most, they come out bursting them. They will then be able to use their membrane to go unnoticed by the immune cells, which try to neutralize the threats. Otherwise, they would be absorbed by phagocytosis, or neutralized by antibodies. It is for this reason that they had to go through the liver before moving on to the next stage of their plan of attack. Thanks to this covering made of liver cells, they can circulate in the blood incognito and infect red blood cells, where they continue to multiply. Eventually, they come out in the same brutal way as with liver cells.
The pieces of cells that end up floating in the circulatory system eventually activate an immune response causing symptoms such as severe fever, cold sweats, seizures and headaches. Less common symptoms include vomiting and diarrhea. If the parasites cross the blood-brain barrier, which absolutely must not be crossed by substances that should not reach the brain, coma can occur, as well as neurological damage and death. After accomplishing their dark intentions, the parasites infect the next mosquito that bites the victim, and the cycle will start again with the next victim. However, if mosquitoes could not be infected with malaria microorganisms, its transmission would be halted and the parasites would die, deprived of food.
Such mosquitoes already exist in the laboratory (and present in nature, but we will talk about them later). They are of the Anopheles Stephensi type, they live in India and are responsible for the transmission of 12% of malaria cases in this country. This means around 106,000 people infected in 2014, not counting the epidemics in Africa that these mosquitoes have caused. All this explains why it is the Anopheles Stephensi that scientists have chosen to modify. Thanks to CRISPR-Cas9, they were able to insert into their genome a gene coding for the production of antibodies specific to malaria. They developed it themselves from human malaria-fighting antibodies, chitinase 1 and the circumsporozoite protein. The latter has a very strange name when it is not known that the sporozoites are the parasites of the malaria in question. In short, the fact is that tests have been conducted, and they show that these modified mosquitoes are indeed incapable of transmitting malaria, because the sporozoites can no longer infect their salivary glands.
What is gene drive, then? Why is it necessary?
But there is still a problem. By the principles of inheritance, transmission of this immunity gene will be less than ideal. Indeed, in the best case scenario, this gene would be dominant. So let’s say an immune mosquito breeds with a natural mosquito (as it should). Their descendants will all be immune, but they will not have both copies of this gene. The problem appears in the second generation, and it becomes even more evident from the following ones. Indeed, half of the descendants will be able to transmit malaria again, and this defeats the goal of eradicating it. We therefore observe that if things are left like this when releasing GM mosquitoes into the wild, it will not be enough to stop it. Thus, we must ask: what to do to fixthe situation?
Gene drive technology would be the solution. Indeed, it makes it possible to “force” a trait to be transmitted to almost all of the descendants of an organism. We use the following method to achieve this. It is very similar to a normal modification using the CRISPR-Cas9 system. In fact, it starts out the same way: you include in a Cas9 the guide RNA from the portion of the genome you want to cut, and when it’s time to replace, that’s where the researchers do something unusual. Instead of inserting in the CRISPR-Cas9 system just the gene that gives immunity to malaria, researchers add to it the guide RNA and the gene that codes for Cas9. It then essentially forms a CRISPR-Cas9 in another CRISPR-Cas9. At the time of genetic shuffling that results in offspring, the integrated CRISPR-Cas9 system will modify the alleles of the wild-type mosquito, which, in theory, would allow the trait to be passed to one hundred percent of the offspring.
In practice, the real rate is not 100%, but rather 99.5%. Scientists believe that with this proportion and a sufficient number of GM mosquitoes released into the wild, the immunity trait would spread very quickly. Speed is what they count on: malaria must not have time to adapt to this mutation, otherwise the whole project would collapse. And again, what consequences would this have for the ecosystem, of which humans are a part?
Yes, what are the risks of releasing GMO mosquitos?
It is indeed necessary to consider the risks and the benefits that the implementation of this project entails, or rather entailed, as to this day, we already have released such mosquitos in Florida. Nothing bad had happened yet, but it’s still interesting to consider what could have gone wrong.
First, it just might not have worked. Then, as mentioned above, the parasites could have adapted, which could possibly have lead to even more harmful effects on human health, mosquitoes, predators, predators of their predators, etc. In short, it would have shaken the ecosystem with consequences that we can only imagine. Moreover, it would be very difficult to fix this error. However, since this gene edit in particular does not bring about a large overall change in the mosquito genome, these two factors constitute all the known risks that the implementation of this project could have posed.
On the other hand, such GMO mosquitoes can bring undeniable benefits. They could save the lives of half a million people each year. In addition, this project is a pioneer in disease eradication. Several others have similar vectors and curbing their transmission would require methods very similar to those that would be employed for Anopheles Stephensi mosquitoes. For example, different types of mosquitoes carry dengue fever and Zika, a disease that causes severe deformities in the fetuses of pregnant women who are bitten. Also, ticks transmit Lyme disease and flies carry sleeping sickness just like fleas carry plague. If we could eradicate all these diseases, we would save millions of human lives every year.
But why don’t we just vaccinate everyone?
It is true that this would be less risky, but there is something else to consider. Even ifa campaign of global vaccination campaign was successful, what about animals? Some species are threatened by malaria. In addition, to date, species are disappearing faster than ever, which is one of the constituents of ecosystem collapse.
In Conclusion… How far we’ve come.
In 2016, the National Academies of Science, Engineering and Medicine published in a report, named Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty and Aligning Research with Public Values, the statement that science was not yet sufficiently advanced to properly determine what were the risks associated with the malaria eradication project, and that it would take about 5 years to ensure the safety of this project. 5 years later, here we are with such mosquitoes released in Florida.
To accumulate enough knowledge to implement this project, it was necessary to study in greater depth the dynamics of populations and the environment. According to Jennifer Kuzma, a scientist at North Carolina State University,
“Gene drive is so different from other genetic modification technologies that it requires a completely new way of thinking about its evaluation […].”
Indeed, until then, the purpose of the tests was to verify that the mutations did not reach the wild population. Now, the opposite is what we are aiming for. However, this quote from University of California vector biologist Anthony James sums up the situation perfectly, and stae what we must, in the end, all remember:
“There is a strong call for caution, but they [the academies] recognize that the promise that science brings is enough to move forward with the gene drive technology. ”
Sources
https://science.sciencemag.org/content/345/6197/626.figures-only
https://www.sciencemag.org/news/2016/06/us-academies-gives-cautious-go-ahead-gene-drive
